Among melanomas affecting the skin, there is marked variation of histopathology and clinical characteristics, partially depending on anatomic site and sun-exposure patterns. It has recently been shown (Curtin, et al., New Engl. J. Med. 353:2135-2147, 2005) that the MAP-kinase and PI3 kinase pathways are activated differently among subtypes of melanoma when tumors are classified according to a combination of UV exposure and anatomic site. Most prominently, while BRAF mutations are highly prevalent (59%) in melanomas occurring on skin without signs of chronic sun-induced damage (non-CSD melanomas), the frequency is very low in melanomas that occur on the palms, soles or subungual sites (acral or mucosal). BRAF mutations are also uncommon in melanomas that occur on skin showing evidence of chronic sun-induced damage (CSD melanomas). About 10 to 20% of melanomas of all subtypes activate these pathways by mutation of NRAS, but mutations of both NRAS and BRAF never occur together. These findings raise the critical question of how the MAP kinase pathway might be activated in those tumors that do not have NRAS or BRAF mutations.
Array CGH analysis by Curtin et al., supra, found differences in the characteristics of the DNA copy number aberrations among the melanoma subtypes, with significant differences in the frequency of involvement of several loci. Examination of the copy number profiles of 103 primary melanomas from this study found gain (10 tumors) or amplification (7 tumors) of chromosome 4p12. Sixteen of these tumors had been sequenced for BRAF and NRAS and no mutations were found. All 17 tumors were of the acral, mucosal, or CSD subtypes.
The common region of 4p12 copy number elevation contains several receptor tyrosine kinases (RTK) that are attractive candidate melanoma oncogenes. These include the v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog KIT, the vascular endothelial growth factor receptor KDR and platelet-derived growth factor alpha receptor (PDGFRA). KIT is an important gene for melanocyte survival and development (Chabot, et al., Nature 335:88-89, 1988; Geissler, et al., Cell 55:185-192, 1988) and subject to oncogenic mutations in a variety of cancer types (Beghini et al., Cancer 92:657-662, 2001; Beghini et al., Blood Cells Molecules and Diseases 24:262-270, 1998; Isozaki, et al., Am. J. Path. 157:1581-1585, 2000; Lux, et al., Am. J. Path. 156: 791-795, 2000; Wardelmann, et al., Mod. Pathology 15: 125-136, 2002). However, previous investigations have generally dismissed its importance in melanoma because expression appeared to be lost during tumor progression (Lassam & Bickford, Oncogene 7: 51-56, 1992; Natali, et al., Int. J. Cancer 52: 197-201, 1992; Zakut, et al., Oncogene 8: 2221-2229, 1993; Huang, et al., Oncogene 13: 2339-2347, 1996; Montone, et al., Mod. Pathology 10: 939-944, 1997). KDR is important in angiogenesis (Millauer, et al., Cell 72: 835-846, 1993) and in the development of solid tumors (Millauer, et al., Nature 367: 576-579, 1994) and is commonly expressed in melanoma (Straume & Akslen, Am J Pathol 159: 223-235, 2001). PDGFRA is found to be activated by mutations or small deletions in a subset of gastro-intestinal stroma tumors (GIST) (Heinrich, et al., Science 299: 708-710, 2003) and in childhood acute myeloid leukemia (Heinrich, et al., Science 299: 708-710, 2003).
Protein-tyrosine phospatases (PTPases) are a highly pleiomorphic set of molecules with roles in regulating responses of eukaryotic cells to extracellular signals by regulating the phosphotyrosine content of specific intracellular proteins. Mammalian PTPases have been divided into two broad categories: (1) transmembrane receptor PTPases which contain linked cytoplasmic catalytic domains, and (2) intracellular PTPases. Within the second category is a PTPase termed SHP2 that contains two tandem SRC homology 2 (SH2) domains located at the amino terminal end of the protein. The SH2 domains enable SHP2 to bind specific phosphotyrosine residues within protein sequences. Mutations within SHP2, most specifically within the SH2 regions of SHP2 have been associated with various disorders including: Noonan Syndrome, LEOPARD Syndrome, Juvenile Myelomonocytic Leukemia, Acute Monoblastic Leukemia and various neuroblastomas. SHP2 operates immediately downstream of KIT and cells expressing mutant SHP-2 have been shown to be sensitized to stem cell factor (SCF), the ligand for KIT, stimulation resulting in a prolonged and more intense signal of p-ERK lasting up to 60 min (Niimi, et al., Leukemia 20, 635-644, 2006).
The current invention is based on the discovery of certain KIT-dependent melanomas, e.g., mucosal, acral, ocular, such as conjunctival, or CSD melanomas.